The field of the invention relates to compounds that function as ligands for estrogen receptors (ERs). In particular, the field of the invention relates to substituted (4′-hydroxyphenyl)cycloalkane compounds that are specific agonists for the estrogen receptor beta (ERβ) and the use of such compounds in pharmaceutical compositions for treating diseases and disorders associated with ER activity.
Estrogens are important regulators of many physiological processes that include reproduction, cognition, cardiovascular health, and bone metabolism. (See, e.g., Deroo et al., “Estrogen Receptors and Human Disease,” J. Clin. Invest. 116:561-570(2006). Based on their widespread role in a number of physiological processes, estrogens have been implicated in a number of diseases and disorders which include cell proliferative diseases and disorders (e.g., breast cancer, ovarian cancer, endometrial cancer, colorectal cancer, and prostate cancer), neurodegenerative diseases and disorders, cardiovascular disease, and osteoporosis to name a few. (See id.). In many of these diseases and disorders, estrogen mediates its effects through the estrogen receptors (ERs).
The ERs exist in 2 main forms, ERα and ERβ, which have different tissue expression patterns. (See Mueller et al. (2001), “Estrogen receptors and endocrine diseases: lessons from estrogen receptor knockout mice,” Curr. Opin. Pharmacol. 1: 613-619). ERα and ERβ are encoded by separate genes, ESR1 and ESR2, respectively, found at different chromosomal locations, and numerous mRNA splice variants exist for both ERα and ERβ. (See, e.g., Hernyk et al., “Estrogen receptor mutations in human disease,” (2004) Endocr. Rev. 25:869-898). Because of their role in estrogen-related diseases, ERα and ERβ have been targeted for development of specific ligands that modulate their activities. The ligand specificity of ERα and ERβ differ, and a ligand that binds and functions as an agonist or antagonist for ERα may or may not bind and function as an agonist or antagonist for ERβ.
One group of ligands for ERs that have been developed are the so-called “selective estrogen receptor modulators” or “SERMs” which include tamoxifen and raloxifene. Tamoxifen and raloxifene have been observed to exhibit tissue-specific estrogenic activity. For example, tamoxifen is an antagonist in the breast and has been a safe and effective adjuvant endocrine therapy for breast cancer for almost 20 years, but tamoxifen is an ER agonist in bone and uterus. (See, e.g., Deroo et al., “Estrogen Receptors and Human Disease,” J. Clin. Invest. 116:561-570 (2006)). Raloxifene exhibits greater agonist activity in bone and less agonist activity in the uterus. (See Fabian et al., “Selective estrogen-receptor modulators for primary prevention of breast cancer,” J. Clin. Oncol. 23:1644-1655 (2005)). Whether a ligand is an ER agonist or antagonist in a particular tissue depends on several factors, including which form of the estrogen receptor predominates in the particular tissue, in other words ERα or ERβ, where the ligand may exhibit different binding affinity and/or agonist/antagonist activity for ERα versus ERβ.
ERα and ERβ agonists have a wide range of biological effects that implicate disease such as cancer and disorders of the central nervous system (CNS). Clinical studies have indicated that administering estradiol (E2) in post-menopausal hormone replacement therapy (HRT) can lead to increased incidence of breast and endometrial cancer. (See Beral et al., “Breast cancer and hormone-replacement therapy in the Million Women Study,” Lancet. 2003; 362(9382:419-27. Epub 2003/08/21. PubMed PMID: 12927427; Gann et al., “Combined hormone therapy and breast cancer: a single-edged sword,” JAMA: the journal of the American Medical Association. United States 2003. p. 3304-6; Li et al., “Relationship between long durations and different regimens of hormone therapy and risk of breast cancer,” JAMA: the Journal of the American Medical Association. 2003; 289(24):3254-63. Epub 2003/06/26. doi: 10.1001/jama.289.24.3254. PubMed PMID: 12824206; and Anderson et al., “Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial,” JAMA: the journal of the American Medical Association. 2004; 291(14):1701-12. Epub 2004/04/15. doi: 10.1001/jama.291.14.1701. PubMed PMID: 15082697). This effect is mediated predominantly by ERα, the dominant isoform present in the mammary gland and uterus. (See Song et al., “Estrogen receptor-beta agonist diarylpropionitrile counteracts the estrogenic activity of estrogen receptor-alpha agonist propylpyrazole-triol in the mammary gland of ovariectomized Sprague Dawley rats. The Journal of steroid biochemistry and molecular biology. 2012; 130(1-2):26-35. Epub 2012/01/24. doi: 10.1016/j.jsbmb.2011.12.018. PubMed PMID: 22266284).
The increased cancer risk has led to decreased usage of HRT in post-menopausal women. But, studies also have shown that HRT can provide a positive effect mediated primarily by ERβ, which is a decrease in the risk of dementia in post-menopausal women. (See Leblanc et al., “U.S. Preventive Services Task Force Evidence Syntheses, formerly Systematic Evidence Reviews. Hormone Replacement Therapy and Cognition. Rockville (Md.): Agency for Healthcare Research and Quality (US); 2002). As such, specific ERβ agonists can provide the CNS benefits of E2 with minimal side effects. However, current SERMs such as tamoxifen and raloxifene, are not specific for ERβ, have carcinogenic side effects, and provide little memory enhancement. (See Yaffe et al., “Cognitive function in postmenopausal women treated with raloxifene. New England Journal of Medicine. 2001; 344:1207-13; and Paganini-Hill et al., “Preliminary assessment of cognitive function in breast cancer patients treated with tamoxifen. Breast Cancer Research and Treatment. 2000; 64:165-76). Safer and more effective treatments can be developed by selectively targeting ERβ.
Thus, new ligands for estrogen receptors are desirable. In particular, new ligands that exhibit selective agonist or antagonist activity for ERβ versus ERα are desirable. These new ligands should be suitable for treating diseases and disorders associated with ER activity, such as cell proliferative diseases and disorders or psychiatric diseases and disorders. Such new ligands are disclosed herein in the form of substituted (4′-hydroxylphenyl)cycloalkane compounds.